Process for the uniform distribution of a drug on a granulated base

ABSTRACT

A METHOD FOR MAKING TABLETS CONTAINING A SOLID BIOLOGICALLY ACTIVE COMPOUND IN NON-GRANULAR FORM FIXED TO THE EXTERNAL SURFACE OF A GRANULAR BASE MATERIAL BY: (A) COMBINING A PREDETERMINED AMOUNT OF SAID BIOLOGICALLY ACTIVE COMPOUND WITH AN INERT VOLATILE LIQUID, (B) CONTACTING SAID LIQID AND SAID ACTIVE COMPOUND WITH AN AGITATED MASS OF SAID GRANULAR BASE, AND (C) REMOVING SAID VOLTAILE LIQUID, (D) DIRECTLY COMPRISING THE COATED GRANULAR BASE TO FORM A TABLE.

. r 3,836,618 PROCESS FOR THE UNIFORM DISTRIBUTION OF 7 A DRUG ON AGRANULATED BASE Robert T. Stevens, Springfield, Pa., assignor toAmerican Home Products Corporation, New York, N.Y. No Drawing. FiledDec. 23, 1971, Ser. No. 211,707 Int. Cl. A61k 9/00; B32b 31/12 Us. 1264-101 8 Claims ABSTRACT OF THE DISCLOSURE A method for making tabletscontaining a solid biologically active-compound in non-granular formfixed to the external surface of a granular base material by:

(a) combining a predetermined amount of said bio- "logically activecompound with an inert volatile liquid, (b) contacting said liquid andsaid active compound with an agitated mass of said granular base, and

(c) removing said voltaile liquid,

(d) directly compressing the coated granular base to form a tablet.

BACKGROUND OF THE INVENTION points of the crystalline solid material andelastic deformation at other solid interfaces leading to decreasedparticle size of the compound and, upon release of the compressionforce, splitting of the slug or tablet matrix as a result of therelaxation of the highly strained pressure bonded (cold bonded)interparticulate adhesive forces.

To overcome these problems, it is conventional in the pharmaceuticalmanufacturing industry to granulate the pharmaceutically active materialwith or Without a substrate or base material of inert nature. Thegranulation process affords a coarse particle which is desireably ofsuch free-flowing character that it will readily fill the tablet diecavity in a tableting machine without the formati'o'riof trapped airpockets. Excessively large granulated particles may present a relativelyintractible fused surface which affects the dissolution properties ofthe drug and, during the fabrication stages of manufacture, require thepresenceof a filler material to fill voids in a tablet dieduringcompression. Thus, the desired particle for drug processing isfree-flowing, presenting a non-fused surface, and of a size that air isnot entrapped although a tablet die is adequately filled while readilycold bonding during compression. The use of an inert material as a basefor a free-flowing granule with which an active drug may be mixed anddirectly compressed into a tablet is conventional. The techniquesemployed today generally involve either wet or dry granulationprocesses.

The wet granulation process commercially employed today involves theperformance of eight distinct processing steps, which are:

(1) blending of dry ingredients; (2) milling the dried blended solidmaterial to the desirable particle size; (3) the preparation of a bindersolution; (4) mixing the blended milled dry ingredients in the bindersolution;

United States Patent "ice 3,836,618 Patented Sept. 17, 1974 (5) afterdrying the solution the material is screened to afford a desired granulesize;

(6) the still moist material is thoroughly dried;

(7) the dried agglomerated material is re-screened to break up any masswhich is too large for subsequent handling; and

(8) blending of the thus formed granules with a lubricant or otherdesired external coating material.

The commercially practiced double compression or slugging proceduresfollowed in the pharmaceutical industry, involve several distinctprocessing steps in which either all or a portion of the granularsubstrate needed for a given recipe is milled and mixed with the activeingredients in the dry state, followed by compaction of the mixture toform a slug which is ground, sieved to separate fines, the fines beingreslugged and converted to granules by repeating the same sequence ofsteps, followed by blending of the granules so produced. Where only aportion of the original granular substrate was mixed with the activeingredients, additional steps are necessary to blend the concentratewith the rest of the granular substrate material after assay of theconcentrate.

Following any of the known techniques for the combination ofpharmaceutical compounds with filler materials to produce compressiblegranules a substantial amount of equipment, labor, fioor space and timeis involved. The double compression (slugging) method was formerlybelieved to be indispensible where unique problems existed requiring theproduction of granulated material for tablets in the complete absence ofwater or abnormal temperatures. To date, the inherent problems attendingdry compaction of crystalline or powdered materials, e.g. the productionof an inordinate amount of fines and loss of uniformity of productconcentration still plague the industry.

BRIEF DESCRIPTION OF THE INVENTION In accordance with this invention,there is provided a process for the uniform distribution of smallquantitites of solid, powdered ingredients upon a directly compressiblegranular base material which comprises combining a predetermined amountof a biologically active compound with an inert volatile liquid,contacting the resulting mixture with a mass of granular base materialin an agitated state, followed by removal of the volatile liquid fromthe mixture, thereby depositing the active ingredient upon the surfaceof the granular base without changing the characteristics of thegranulated base material. Thus, the process of the instant inventionprovides for the direct addition of active ingredients; e.g. active drugsubstances, etc. to a base material while retaining the free-flowcharacteristic, the direct compression characteristic and the originalparticle size distribution of the granular substrate. Thus, by theprocess of the instant invention, the direct production of a drug tabletmay be performed in the operative steps of (1) preparation of a solutionor suspension of the pharmaceutical of granulated material are no longeressential to the production of a more uniformly distributedpharmaceutical material than was heretofore obtainable. Moreover, atablet mixture employing the external method of drug addition to thegranular base can provide tablets with improved dissolution rates overtablets made from mixtures using the slugging method of preparation. I

Other and equally important advantages afforded by the external methodof drug application provided by the process of the instant invention, isthe improved distribution of the drug over the base material. In thecase of dry blending of drug and substrate materials, replication ofdrug content uniformity is difficult if not unachievable in batchoperations. This is especially true where repeated blending andreblending as well as multiple milling and grinding steps produces arelatively large quantity of fines. The inordinate concentration ofactive drug materials in the fines of any given granulation batch isbelieved to result from the initial poor mixing properties of a finecrystalline or powdered material with a large granulated substratematerial, or, in the case of the wet granulation procedure, it isgenerally considered that upon drying, the solvent as it leaves thegranule matrix carries with it the soluble drug material and leaves anuneven deposit on the surface of the granule base, which upon blendingwith additional amounts of inert granular material tends to be erodedand appear in relatively high percentages in the composition fines.

In the concentrate method of granule preparation in which the activeingredient is uniformly mixed with a portion of the granular basematerial followed by various slugging and reslugging steps and anultimate blending with the rest of the inert base recipe, theconcentrate granules and the granule substrate are of similar dimension,but differ in appearance. The granular substrate is oft times uniformlyrough on all surfaces Whereas the concentrate exhibits one surface whichis fiat and smooth. The flat surface of the concentrate granule isbelieved to represent a portion of the slug surface which was fracturedduring grinding. The achievement of uniform drug distribution throughoutthe composition produced by the concentrate method is poor as a possibleresult of the fact that the concentrate particle presents one flatsurface whereas the granular substrate does not.

DETAILED DESCRIPTION OF THE INVENTION The instant invention is based onthe discovery of a means for preparing pharmaceutical compositionssuitable for tableting by combining active drug ingredients with agranular substrate. The granular substrate may range in particle sizefrom about 10 to 200 mesh (US. Standard Sieve), preferably about 12 to50 mesh. The percentage by weight of granular substrate lies in therange from about 60 to 99.9 percent, preferably within the range ofabout 80 to 99.9 percent. The percentage by Weight of the externallyadded drug material based upon the weight of the particulate substrategranule may be from approximately 0.1 percent to about 40 percent,preferably up to 20 percent.

To achieve uniform distribution of the drug on a granular substrate, anyinert volatile solvent or diluent may be employed which is not a solventfor the granular substrate, such as a lower alcohol containing from 1 to3 carbon atoms, chloroform, methylene chloride, acetone, and the like.Generally, it has been found that from about 5 to 33 percent by weight,preferably from to about percent by weight based upon the weight of thegranular substrate, is a suitable quantity of solvent for dissolution ordispersion of the drug without providing an excessive amount of liquidfor subsequent removal. It is preferred that a solvent be selected inwhich the drug is soluble. However, a fine dispersion of the drug in adiluent provides acceptable results. If additional additives are desiredto be added to the granular substrate, such as one or more activepharmaceutical compounds, a dye or pigment, a disintegrant, anabsorbent, a sweetener, or a lubricant, it is preferred that thesecomponents be introduced simultaneously with the application of thedesired drug material all in combination with the same solvent ordiluent. It is not necessary that each additive component be completelydissolved in the volatile material, some maybe dissolved While theothers appear in a dispersed state.

The dissolved or suspended drug and/OrotheraddF tional ingredients, maybe sprayed or poured by suitable means onto the mixing or agitatedmassof granular substrate material. Mixing of the granular substrateduring. the addition of the active drug material in its liquid carrier,should be maximized While maintaining a very low rate of attrition ofthe granular substrate material. To achieve this it is preferred toemploy a twin cone or twin shell blender or a single blade sigma mixerin which the mixing function may be optimized by sealing the mixingchamber and providing jacketed heating and/or cooling means as well as avacuum system for removal of the wire tile solvent. The preferred mixeris a twin shell blender fitted with a water jacket, vacuum system,condenser and a liquid/ solid dispersion device. I

In practice, the granular substrate is charged in the. mixer and theunit is sealed. The drug to be distributed on the substrate material isdissolved or suspended in the solvent of choice. The granular substanceis blended and the drug/ solvent mixture is added through a liquid/soliddispersion device. When all of the drug/solvent mixture has been addedto the blending substrate, the vacuum system is activated and solvent isstripped from therniX ture. After complete solvent removal, the dryproduct mixture is discharged from the mixer. The resultant granulatedmaterial exhibits very little change in particle'size distribution fromthat of the originally charged substrate and may be directly transferredto a tablet press for compression into tablets. The following specificexamples are presented for the purpose of illustrating the method forpreparing one layer of a two layer tablet or a tablet existing as asingle entity by external addition of an active drug material to agranu-- lar substrate. These examples are not to be construed aslimitations on the scope of the invention, since it is ap parent thatthe production of compressible granular par ticles containing externallyapplied drug material may form the basis for uniform, reproduciblereadily 'diss'olvable pharmaceutical compositions for encapsulationrathef than tableting.

In the following examples the expressions U.S.P. means United StatesPharmacopeia Grade Reagents, the quantii ties expressed are in terms ofweight percent of the named compenent to the Whole, N.F. means NationalFormulary, the measurements of pressure are given in inches of mercury,absolute, the expression RD. and C. stands for an approved Food, Drugand Cosmetic and the amount of diluent or solvent employed was thatsuflicient to suspend or dissolve the material to be applied to thegranular base material.

EXAMPLE I Tablet Composition Percent"l0-(2-dimethylaminopropyl)phenothiazine 5-6 Aspirin 94-95 Chloroform,N.F. l

Transfer the aspirin in granular form to a's ingle blade sigma mixer.Dissolve the phenothiazine in chloroform. While mixing the aspiringranulation, add the drugchlo'roform mixture through a perforated tube.Dry the'granulation with vacuum of 30 inches Hg. Discharge thegranulation and compress.

EXAMPLE II Following the procedure of Example I, with the exception thata diluent (acetone) is substituted for the solvent, the tablet isproduced as follows: Transfer the aspirin granulation to a single blademixer. Add the phenothiazine to the acetone and stir to susupend. Addthe susupension to the aspirin granulation while mixing, then dry.Discharge the granulation and compress.

EXAMPLE III Percent l0-(Z-dimethylaminopropyl)phenothiazine 0.5-1.5Sodium Saccharin, N.F. 1.05.0 Aspirin 93.5-98.5 Methanol Alcohol.

Add the'aspirin granules to a twin shell blender. Dissolve thephenothiazine in the methyl alcohol, then add and suspend the sodiumsaccharin in the methyl alcohol solution. Add the solution/suspension tothe blending aspirin granules, then dry in vacuum. Discharge thegranul'ation and compress.

EXAMPLE IV Percent d1 13-B-ethyl-17-a-ethinyl-17-;8-hydroxygon-4-en-3-one .05-5.0 Pigment, yellow .l0l.0 Cellulose Binder 10.0-40.0Lactose 5090 Tablet Disintegrant .52.0 Lubricant .11.0 Chloroform.

Transfer the lactose and cellulose binder to a twin shell blender.Dissolve the progesterone in the chloroform then add and suspend theyellow dye. Add the drug/dye/solvent mixture to the lactose andcellulose binder. D-ry in vacuum, add the disintegrant lubricant andblend. Discharge the granulation and compress, using conventionalfeeding systems.

EXAMPLE V A tablet containing more than one pharmaceutical is readilyproduced, for example, by reducing the amount of the progesterone inExample IV to from about 0.05 to about 1.5 percent and using, in mannerotherwise identical to the technique employed with progesterone, from 15to about 35 percent by weight estrogen(19-nor-17-apregna-1,3,5,(l0)-trien-20-yne-3,17-diol) as follows:

Transfer the cellulose binder and lactose to a twin shell blender.Dissolve the progesterone and estrogen in the chloroform and add it tothe cellulose/lactose mixture. Dry in vacuum, then add the binder andlubricant and blend. Discharge the granulation and directly compressinto tablets.

The following tabular comparison of an externally added drug combinedwith a granular substrate versus granular products produced by theconcentrate: or total slugging" method shows the improved distributioncharacteristics obtained by the process of the instant invention.

Table II illustrates the screen analysis of granulated compositionsprepared by the concentrate slug, the total slug method and externalapplication method of the instant invention. In each case, the activeingredient and the same additional granular substrate material wasemployed.

TABLE II Screen analysis of a granular substrate and an externally addedactive ingredient vs. slugging method. [Screen analysis: percentretained (U.S. standard Sieve Granular Concensubstrate trate TotalGranular external slug slug substrate adds method method Mesh No.:

16 0. 05 0. 53 13. 34 1.08 99. 25 90. 49 61. 46 70. 43 0. 51 5. 8 21. 2714. 0. 06 0. 58 0. 91 1. 62 0. 07 1. 09 1. 03 3. 09 200 0. 02 0. 73 0.78 2. 87 Pass 200 0. 01 0. 60 1. 20 5. 89

In each example above, 10 gm. samples were randomly selected from finalgranulations and tested in a Sonic Sifter.

From this analysis, it is clear that the particle size remainssubstantially constant in the process of this invention as opposed tothe slugging method of particle preparation.

Since the dissolution rate of a drug substance from a dosage form is ameasure of the rate of solution of the drug, this rate is oftenconsidered to be the critical attribute of a specific dosage form forpresentation of that specific drug to the gastrointestinal fluids of thehost. The following Table III presents comparative dissolution rates inwater of a specific drug formulation produced by the method of theinstant invention as well as the concen-. trate slug method and thetotal slug method. As may be clearly seen from the data presented, thedissolutio't rate of the granules formed in the slugging methods wasslow, possibly because the drug was tightly bound in the compactedaggregate and rapid and/or total release or dissolution was therebyinhibited.

Furthermore, Table III presents comparative disintegration data, thelatter being the time required for a tablet to break down into particlessufiiciently small to pass a ten mesh screen. In operation, the testingof a tablet for disintegration is performed by placing the tablet in asmall cylinder having a ten mesh screen at the bottom. The cylinder ismoved up and down in water at 37 C. to simulate in vivo agitation. Thedisintegration time is assumed to be the time in which the tablet wouldbreak apart in the stomach of a host. In these experiments, the granularmaterial used as a substrate was also TABLE I Assay results ofgranulations prepared by externally added active ingredients vs.slugging methods Concentrate slug Externally added drug method Totalslug method Trial No 1 2 3 4 5 6 7 8 9 10 id C.V. :1; ercent 1.3 0.6 0.91.0 4.8 10.7 8.8 2.4 1.5 1.8 iggi l gsii y ig r h g p ereggf claim"?"a..." 100. I 99. 9 99. 1 100.6 97. 6 104. 7 96. 7 99. 0 100. 0 99. 0

In each trial, 10 samples were randomly removed from an activeingredient which was combined with B a second the finished bulk materialand assayed. The content uniformity is indicated as a coeificient ofvariation (C.\ The percent of Claim is based upon the theoretical amountof the drug that should be present based upon the amount used (percentof theory).

active ingredient.

In Table III, the expressions T50 and T represent the times in minutesin which 50% and 80% of the drug from the tablets dissolved. Likewisethe percent of each compound dissolved in thirty and sixty minutes ispresented.

TABLE III Externally added drug Concentrate slug method Total lug methodA B A B A B A B A B A B Trial No 1 2 3 4 5 6 Dissolution:

Percent minutes 95 93 97 92 76 101 88 89 88 95 76 91 Percent 60 minutes97 95 97 95 88 103 91 99 93 98 86 9 Disintegration Ags.: V

W./disks, mi notes" 8 6 l4 1 1% 12 15 Hardness, kg 22-24 20-24 2-3 202024 23-24 Disintegration Time in Artificial Gastric Solution W/D; U.S.Pharmacopoeia XVIII, Sept. 1, 1970 pp. 932-934.

What is Claimed is:

1. A process for preparing medicament containing tablets consistingessentially of:

(a) providing a granulated base material which is free flowing and of acharacter that it will readily fill a tablet die cavity on a tablettingmachine without the formation of trapped air pockets while readily coldbonding during compression;

(1)) combining a predetermined amount of a biologically active compoundwith an inert volatile liquid which liquid is not a solvent for thegranular base;

(0) contacting said liquid and biologically active compound With anagitated mass of said granular base material to externally deposit saidactive compound on said base material;

(d) removing said volatile liquid to obtain a coated granulated basematerial containing from 0.1 to about 40 percent by weight of saidbiologically active compound;

(e) directly compressing said coated base material to form a tablet.

2. The process of Claim 1 in which said inert volatile liquid is asolvent for said biologically active compound.

3. The process of Claim 1 in which said mass of granular base ismechanically agitated while said mixture of volatile liquid andbiologically active compound is applied thereto as a spray.

' ene-3,17/3-diol.

References Cited UNITED STATES PATENTS 3,079,303 2/1963 Rail 42435 X3,200,039 8/1965 Thompson 424-361 X 3,344,030 9/1967 Stevens 42436l X3,539,380 11/1970 Johnson 42435 X 3,691,090 9/1972 Kitajiima 42435 X2,798,837 7/1957 Sahyun 42435 2,877,159 3/1959 Lachman 264l01 X ROBERTF. WHITE, Primary Examiner T. P. PAVELKO, Assistant Examiner U.S. Cl.X.R.

